Derivatives of hexestrol



Patented 'Mar. 28, 1950 DERIVATIVES F nnxns'rnor'.

Emil Kaiser and Jerry Svarz, Chicago, 11]., al-

sirnors to Armour and Company, Chicago, 111., a corporation of Illinois No Drawing. Application June a, 1946,

Serial No. 674,929

3 Claims.

This invention relates to derivatives of hexestrol, more particularly to the allyl derivatives of hexestrol and to methods for their preparation. These new derivative compounds have estrogenic activity in varying degrees and are useful in the synthesis of various useful substances.

We find that hexestrol may be reacted with allyl halides to prepare a diallyl ether of hexestrol. This reaction may be carried out in the presence of an alkaline compound capable of reacting with the halogen element of the halide. Examples of such alkaline compounds are p0- tassium carbonate, calcium carbonate, sodium hydroxide, or barium hydroxide. Preferably, the reaction is conducted in an organic solvent which is not reactive with the diallyl ether product. Examples of such organic solvents are methylethyl, ketone, acetone, benzene, and the like.

' We may use any allyl halide, either the bromide, iodide, or chloride, and preferably in slight excess over the theoretical amount required. The hexestrol and allyl halide may be mixed in the I solvent and heated for several hours to complete the'reaction. The diallyl ether product may be recovered suitably by diluting the reaction product with water, extracting the precipitate with ether, drying the extract, and crystallizing from methanoL- Other uitable methods of recovery and purification may be used.

The reaction is described by the following formula:

produced may suitably be cooled and dissolved in a dilute alkali solution. The alkali solution may be filtered and acidified as with hydrochloric 46 acid, and after a solid precipitate has formed. the 3,3 allyl hexestrol may be filtered off, washed with water, and crystallized from an organic solvent such as nitromethane. Any suitable method of purification may be employed instead of 60 the procedure just given.

The reaction to prepare 3,3 allyl hexestrol is described a follows;

0 :Ha C 3H J I beat H; 0 -C O 0 3H; --v

I l inert atmos. H H

1 CzHn HO OH H A H: H: tn in We have further found that 3,3 allyl hexestrol may be converted to 3,3 propenyl diethylhexestrol by heating in the presence of an alkali, potassium hydroxide, or sodium hydroxide. For example, in carrying out this reaction we prefer to dissolve the alkali and 3,3 allyl diethylhexestrol in an organic solvent. Yields may be improved by adding to the solution a small quantity of a hydrosulfite salt, such as sodium hydrosulfite. The solution containing the reactants may be heated in an inert atmosphere until the reaction is completed and the reaction product then recovered. When the temperature is held at about 0., about two hours is sumcient to complete the reaction. Recovery and purification can be done by any of the well understood procedures.

01H CaHl The reaction to prepare the 3,3 propenyl hexestrol is described by the following formula:

We further find that either the 3,3 allyl hexestrol or the 3,3 propenyl hexestrol may be reacted with hydrogen to prepare 3,3 propylhexestrol. This is accomplished by agitating the 3,3 allyl hexestrol or 3.3 propenyl hexestrol in a solvent with hydrogen under pressure and in the presence of a catalyst such as platinum.

The reaction to prepare 3,3 propyl hexestrol from 3,3 allyl hexestrol is described as follows:

It will be observed that 3,3 propenyl hexestrol has the double bonds of its side chain in conjugated relation with the double bonds of the aromatic nuclei. The compound is susceptible to light and turns yellow upon exposure.

Specific examples of the preparation of allyl derivatives of hexestrol follow:

EXAMPLE 1 Preparation of the diallyl ether of hexestrol 13.4 grams of hexestrol was dissolved in 40 cc. of methyl-ethyl ketone. 14.0 grams of anhydrous potassium carbonate and 12.1 grams of allyl bromide were added to the solution and the whole mixture refluxed for 7 hours. Then the methylethyl ketone solution, without filtration, was diluted with water. The precipitate, which was formed by the dilution, was extracted with ether, the ether washed with a alkali solution and then with water. The ether solution was dried with sodium sulfate, evaporated to dryness and the residue crystallized from methanol. 9.5 grams of crystalline hexestrol allyl ether was obtained having a melting point of 81.5 C.

' EXAMPLE 2 Preparation of thediallzll ether of hexestrol ether "layer was washed twice with 'a 10% potasdrocholoric acid. The oily solution precipitated overnight and was filtered of! and washed with water. After drying there was obtained 6.1 grams of crude 3,3 allyl hexestrol. The crude material was crystallized from nitro methane.

' EXAMPLE 4 Preparation of 3,3 allyl hexestrol was treated with a 10 potassium hydroxide solution and the cloudy alkaline solution clarified by filtration with a small amount of charcoal. The filtrate was acidified with hydrochloric acid. An oily precipitate settled out. The precipitate solidified after standing overnight and was filtered off. The substance was dried in vacuum desiccator and then dissolved in 20 cc. of ether, and low boiling petroleum ether added until cloudiness developed. The cloudy solution was kept overnight at -5 C. A sticky brown precipitate settled out and was removed by filtration. The almost colorless filtrate was concentrated and several volumes of petroleum ether added. By cooling to 5-10 C., a crystalline precipitate was formed which was filtered off. In a similar manner more material was crystallized out from the motor liquor. The combined fractions weighed 5.3 grams and melted at 107 C.

Anal.Calcd. for C24H30022 C, 82.25%; H, 8.62%. Found: C, 82.30%; H, 8.67%.

EXAMPLE 5 Preparation of 3,3 propenyl hexestrol Nine (9) grams of potassium hydroxide was dissolved by heating and stirring in 50 cc. diethylene glycol. 4.5 grams of 3,3 allyl hexestrol, prepared as in Example 4, together with 0.3 gram of sodium hydrosulfate dissolved in 2 cc. of water was added to the diethylene glycol solution. The reaction mixture was kept in an oil bath of 170-180 for two hours in an atmosphere of nitrogen. After cooling the solution was diluted with water, acidifiedwith hydrochloric acid and extracted with ether. The ether layer was washed with water, dried and concentrated by heating and bubbling nitrogen through the solution. -To the concentrated ether solution petroleum ether was added until cloudiness de- *dark oil settled out which was discarded. The

sium hydroxide solution and thenwith water.

The ether solution was dried and then evaporated. The residue was crystallized twice from iso propanol. The diallyl ether of hexestrolcrystallized in shiny needles and the melting point was found to be 81.5 C. The yield was 9 grams.

'Anal.calcd. for C24H3o022 82.25%; H, 8.62%.

Found: C, 82.05%; H, 8.37%.

cooled and dissolved in 5% alkali solution. The 1 yellow upper layer was .-poured off and treated again withvpetroleumlether. This procedure was repeated until the upper layer became colorless."

This upper layer was then concentrated in a nitrogen atmosphere, to asmall volume. 'Pe-. troleum ether'was addedand the solution kept a at 5-10 C. The 3,3 propenyl hexestrol crystallized out, and'was recrystallized from a mixture ofether-petroleum ether. The melting point of the 3,3 propenyl hexestrol was 153-154" C.

Anal.---Calcd.-v for C24H30O22 EXAMPLE 6 Preparation of 3,3 propylhexestrol 0.2 g. of platinum oxide was suspended in cc. of isopropanol and shaken with hydrogen at p c, 22.25%; H." 8.62%. Found: 0, 82.01%;H, 8.54%.

asomaas 45 lbs. pressure. Then 0.5 g. of 3,3 allylhexestrol was added and shaken with hydrogen at 45 lbs. pressure for 8 more hours. The solution was filtered oil and evaporated. The residue was crystallized from an ether petroleum ether mixture M. P. 123.5-1245" C.

Anal.Calcd. for CuHuOa: C, 81.31%; H, 9.83%. Found: C, 81.58% H, 9.49%.

EXAMPLE 7 Preparation of 3,3 propylhezestrol 8. A compound having the formula cm. can

HoQH HQ0s wherein R is an unsaturated aliphatic radical having 3 carbon atoms.

EMIL KAISER. JERRY SVARZ.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 1,787,036 Ehrlich Dec. 30, 1930 2,284,369 Caplan May 26, 1942 20 2,385,472 Schmelkes Sept. 25, 1945 FOREIGN PATENTS Number Country Date 24,932 Germany Jan. 22, 1914 

3. A COMPUND HAVING THE FORMULA 